1. Field of the Invention
The present invention is broadly concerned with methods of forming substituted guanidines utilizing nickel catalysts. More particularly, the methods comprise guanylating amines or pyrrolidines with guanylating agents such as thioureas or isothioureas in the presence of a nickel catalyst. Preferably, the nickel catalyst comprises nickel in the zero oxidation state. Suitable Ni(0) catalysts are preferably derived from nickel-boride alloys, nickel-phosphide alloys, aluminum-nickel alloys, nickel on kieselguhr, nickel on silica/alumina, and other nickel catalysts.
2. Description of the Prior Art
The guanidine functional group is an important structural component in many biologically active compounds. Due to their strongly basic character, guanidines are fully protonated under physiological conditions. The positive charge thus imposed on the molecule forms the basis for specific interactions between ligand and receptor or between enzyme and substrate, mediated by hydrogen bonds and/or electrostatic interactions. As a result, the guanidino group has been incorporated into many clinically useful drugs. For example, the guanidino group is used in H.sub.2 -receptor antagonists such as cimetidine and tiotidine which are anti-ulcer agents. The guanidine functional group is also found in cardiovascular drugs (e.g., clonidine, guanethidine), anti-diabetic drugs (e.g., phenformin, metformin), anti-malarial drugs (e.g., chloroguanidine), antibacterial agents (e.g., streptomycin), as well as other drugs.
Due to their importance in drug development, synthetic procedures for the preparation of guanidines under mild reaction conditions and in high yields while using minimal amounts of reagents are of significant interest to the pharmaceutical industry. Mild reaction conditions are necessary during the synthesis process because harsh conditions will lower the yield of the reaction product due to decomposition or unwanted side reactions of the valuable drug precursor. Reducing the number and quantity of reagents minimizes the quantity of reagent by-products generated which must be removed from the drug product, thus resulting in decreased drug production costs. Finally, of particular importance are chemical synthesis methods that minimize or eliminate the use of toxic reagents or catalysts, particularly in large scale industrial drug production.
Typically, synthesis of guanidines involves treating amines with guanylating agents. The most commonly used agents include derivatives of pyrazole-1-carboxamidine, aminoiminomethanesulfonic acid, S-methylisothiouronium salts, S-alkylisothioureas, and protected thiourea derivatives.
Substituted and protected thioureas are widely employed in the preparation of substituted guanidines. Coupling reagents (e.g., Ph.sub.3 P/CCl.sub.4 and thiophilic metal salts such as HgO/S, HgCl.sub.2, CuCl.sub.2, and CuSO.sub.4) have been extensively used in conjunction with thioureas for the guanylation of both aliphatic and aromatic amines. The initial step in these reactions involves the formation of intermediate carbodiimides which will then react with amines to give the corresponding guanidines. However, these reactions generally require an excess amount of reagents and/or longer reactions times in order to provide acceptable yields of the particular substituted guanidine. Furthermore, a distinct disadvantage to the use of mercuric salts in guanylation reactions is that the mercuric salts are toxic compounds. Finally, it is very difficult to separate the guanidines from the unreacted mercuric salts and the mercuric sulfide byproduct.
N-Unsubstituted S-methylisothioureas are useful for guanylating aliphatic primary and secondary amines. However, N-alkyl substituted S-methylisothioureas are inadequate at guanylating aliphatic primary and secondary amines due to the fact that this reaction is reversible and the byproduct methyl mercaptan must continually be removed from the reaction mixture in order to drive the reaction to completion.
There is a need for methods of guanylating amines in high yields which do not require the large quantities of coupling reagents and bases used in prior art methods.